Malaria is the best known protozoal disease, caused by one of four species of the sporazoa type—Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. It is one of the most common infectious diseases in at least 100 tropical and subtropical countries in Africa, Southeast Asia, and South America. Worldwide, malaria infects 225 million people and kills about 791,000 in a year. The increasing prevalence of multiple drug resistant strains in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. Although drug resistance is a common problem in the treatment of most microbial infections, malaria and many neoplasms, the impact is more acute for malaria chemotherapy because of the limited number of clinically useful anti-malarial drugs.
Only six prescription drugs are available in the US for treating and/or preventing malaria: Atovaquone/proguanil, Doxycycline, Mefloquine, Primaquine, Chloroquine phosphate, and Hydroxychloroquine sulfate. All of them are discovered more than 40 years ago. Serious side effects are common. Primaquine is the only available causal prophylactics. It has a low therapeutic index. The use of chloroquine is limited because of the worldwide emergence of drug-resistant strains of P. falciparum and P. vivax. Proguanil has a short half-life and strains of P. falciparum resistant to proguanil are common. The newest antimalarial drug Mefloquine was developed in the late 1960s. It is initially reserved by WHO for use in regions where drug resistance to chloroquine is a serious problem. However, problems have arisen with mefloquine use. The cure rate for mefloquine-sulfadoxine-pyrimethamine treatment of P. falciparum in Southeast Asia fell from 96% in 1985 to as low as 50% in 1990. Mefloquine can also produce adverse neurological and psychiatric reactions. Artemisinin and its derivatives are currently under development. However, these compounds cannot be used during pregnancy since they have shown fetotoxicity in rodent models. Artemisinins do not interfere with hepatic stages of parasite development and therefore have no causal prophylactic value.
Therefore, novel medicinal agents are urgently needed to overcome the emergence of resistance and to control an ever-increasing number of epidemics caused by the malaria parasite.
For decades, natural products have been a wellspring of drugs and drug leads. According to a survey, about 61% of the 877 small-molecule new chemical entities introduced as drugs worldwide during 1981-2002 can be traced to or were inspired by natural products. These include natural products (6%), natural product derivatives (27%), synthetic compounds with natural-product-derived pharmacophores (5%), and synthetic compounds designed on the basis of knowledge gained from a natural product (23%). In certain therapeutic areas, the productivity is higher 78% of antibacterials and 74% of anticancer compounds are natural products or have been derived from, or inspired by, a natural product.
Carica papaya L., a perennial tropical tree, belongs to the family of Caricaceae, and is commonly known as papaya, paw paw, kates, or papaw. Carica papaya L. is widely grown in tropical regions, including Central America, the Amazon region, and the Florida, Hawaii, Puerto Rico of the United States, for its edible fruit known as papaya. The fruit is high in vitamin A and is consumed fresh when ripe while the green fruits are grated in salads or boiled like squash. The green fruit of papaya is the source of the enzyme papain, which is used in meat tenderizers and many other biologically active phytochemicals. The leaves of papaya are divided into several lobes, which radiate like the fingers of the hand. In Suriname's traditional medicine, the boiled green leaves of papaya are used against malaria and as an anthelmintic, the seeds as a vermifuge and tea of the fallen leaves against hypertension. The decoction of the leaves has also been used as a treatment for intestinal parasites.
An ethanol extract of the dried leaves of Carica papaya L. exhibited considerable in vitro antimalarial activity to warrant fractionation. On the basis of the initial activity of crude extracts, attention was focused on the bioactivity-guided fractionation of the EtOH extract of the dried leaves, which resulted in the isolation of one new antimalarial natural product, Formula I. Its chemical structure is shown in FIG. 1. Derivative compound, Formula A, was then synthesized from the original natural product Formula I. This derivative compound is orally active against both sensitive and multidrug resistant malaria strains and possesses good therapeutic indices. The chemical structure of the natural product derivative, Formula A, is shown in FIG. 2. The synthesis route is shown in FIG. 3.
Derivative compound (Formula A) underwent biological assessment against six strains of P. falciparum. This compound exhibited superior and equally potent antimalarial activity against chloroquine sensitive and resistant malaria strains.
In mice models, Formula A has shown excellent blood schizonticidal activity and oral prophylactic activity. Mouse model studies also indicate that new compound is much less toxic than existing antimalarial drugs (chloroquine, mefloquine and artemisinin derivatives) and is expected to possess wide therapeutic windows.
The present invention relates to new, more active and less toxic natural product derivatives for the treatment of malaria.